The term avermectin (previously referred to as C-076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The avermectin compounds are a series of macrolides, each of which is substituted thereon at the 13-position with a 4-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity.
The avermectin series of compounds isolated from the fermentation broth have the following structure: ##STR1## wherein R is the 4'-(.alpha.-l-oleandrosyl)-.alpha.-l-oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and PA0 R.sub.3 is methoxy or hydroxy. PA0 R.sub.2 is methyl, ethyl, isopropyl or sec-butyl; PA0 R.sub.3 is OH, loweralkoxy, or loweralkanoyloxy PA0 R.sub.4 is H, OH, or ##STR4## and Y is .dbd.O,--NH.sub.2,.dbd.NOH,.dbd.N--NH.sub.2,.dbd.N--NHC.sub.6 H.sub.5, .dbd.N--NHCONH.sub.2, and .dbd.N--NHCSNH.sub.2,.dbd.NOR.sub.5 or --NHR.sub.5 wherein R.sub.5 is loweralkyl; and the trisubstituted silyl protected derivatives thereof. PA0 13-oxo-22,23-dihydro avermectin B1a/B1b aglycone; PA0 13-oxo-avermectin B1a/B1b aglycone; PA0 13-oxo-milbemycin .alpha..sub.1 ; PA0 13-oxo-milbemycin .alpha..sub.3 ; PA0 13-oxo-avermectin B2a/B2b aglycone; PA0 13,23-dioxoavermectin B2a/B2b aglycone; PA0 13-deoxy-13-methoxyimino-22,23-dihydro avermectin B1a/B1b aglycone; PA0 13-deoxy-13-methoximino-22,23-dihydro avermectin B2a/B2b aglycone.
There are eight different major avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, and B2a based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a Double Bond sec-butyl --OCH.sub.3 A1b Double Bond iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2B --OH iso-propyl --OCH.sub.3 B1a Double Bond sec-butyl --OH B1b Double Bond iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
In the isolation of the avermectin compounds from the fermentation broth, which serve as starting materials for the instant processes, the various avermectin compounds will be found to have been prepared in unequal amounts. In particular an "a" series compound will be prepared in a higher proportion than the corresponding "b" series compound. The difference between the "a" series and"b" series is constant throughout the avermectin compounds and consists of a sec-butyl group and an iso-propyl group respectively at the 25 position. This difference, of course, does not interfere with any of the instant reactions. In particular it may not be necessary to separate the "b" components from the related "a" component. Separation of these closely related compounds is often not practiced since the "b" compound is present only in a small amount, and the structural difference has negligible effect on the reaction processes and biological activities.
In particular it has been found that the starting materials for the compounds of this invention are very often prepared in a ratio of about 80% to 95% avermectin B1a or A1a and less than 20% avermectin B1b or A1b. Thus the preferred composition of this invention is one which contains not less than 80% of the "a" component and not more than 20% of the "b" component.
Milbemycin compounds are similar to the above avermectin compounds in that the 16-membered macrocyclic ring is present. However, such compounds have no substitution at the 13-position and have a methyl or ethyl group at the 25-position (the position the R.sub.2 group is found in the above structure). To the extent that such milbemycin compounds can be oxidized to the 13-keto derivative and converted to the 13-imino and amino derivatives, they are to be construed as being within the ambit of this invention. Such milbemycin compounds and the fermentation conditions used to prepare them are described in U.S. Pat. No. 3,950,360. In addition, 13-deoxy-avermectin aglycones are prepared synthetically from the avermectin natural products and are disclosed in U.S. Pat. Nos. 4,171,314 and 4,173,571. Such compounds are very similar to the milbemycins differing from some of the milbemycins in having an isopropyl or sec butyl rather than a methyl or ethyl group at the 25-position.